Brain stroke ranks as the third leading cause of death and disability in most developed countries (Wolfe et al., J. Neurol. Neurosurg. Psychiatry 72:211 (2002), and is the second most common cause of death worldwide (Murray et al., Lancet 349:1269 (1997)). About ⅙ of all human beings will suffer at least one stroke in their lives (Seshadri et al., Stroke 37:345 (2006)). Stroke can be hemorrhagic, ischemic, or embolic in origin. Each year, 500,000 new cases of brain strokes are reported in the US (Higashida et al., Am. J. Neuroradiol. 26:2323 (2005)). Depending upon the particular cerebral vessels involved, stroke patients may have a one-year mortality rate ranging from 60% to 8% (Murray et al., Lancet 349:1269 (1997); Salgado et al., Stroke 27:661 (1996)). Nonetheless, the surviving stroke patients usually remain severely disabled and require constant care for the rest of their lives.
Despite tremendous effort in thrombolysis and neuroprotection, no effective treatment is available for cerebral stroke in clinical settings. This is largely due to the inability of current treatments to repopulate the stroke lesion cavity with functional neurons and glial cells, which dynamically participate in cell-cell signaling and provide sustained trophic support that is critical for decreased neural degeneration and sustained functional recovery. In support of this notion, neural transplantation strategies have been developed to reconstruct the stroke lesion cavity. Despite its efficacy in providing sustained functional recovery in other types of central nervous system (CNS) injuries, neural transplantation for cerebral stroke repair has had limited success, due to poor donor cell survival and functionality at the infarct site (Savitz et al., NeuroRx 1:406 (2004)).
An accumulating body of evidence has indicated the predominant role of glial scar tissue in obstructing brain tissue regeneration and structural repair following stroke (Lipton, Physiol. Rev. 79:1431 (1999); Gartshore et al., Exp. Neurol. 147:353 (1997)). The dense scar tissue outlining a stroke lesion cavity typically consists of endogenous and/or hematogenous inflammatory cells embedded within a dense, remodeling extracellular matrix (Fitch et al., J. Neurosci. 19:8182 (1999); Lindsay, Reactive gliosis. In: Fedoroff S, Vernadakis A, editors. Astrocytes Orlando: Academic Press; 1986. pp. 231-262; Preston et al., J. Neurotrauma 18:83 (2001)). The presence of the scar tissue not only contributes to regenerative failure, but also to the poor survival and functionality of transplanted cells, and poses a diffusive barrier that hinders the effective delivery of nutrients, oxygen, and pharmacological agents into the lesion cavity.
Since any reparative therapy designed to regenerate brain tissue following a stroke will take place in the lesion site, there is a critical need for strategies to overcome the inhibitory scar and promote neuronal regeneration and reconstruction across the lesion cavity. Most importantly, a well-structured vasculature network that completely re-fills the stroke lesion cavity is a prerequisite to support the brain tissue regeneration process.
Spinal cord injury (SCI) continues to affect a significant number of individuals, especially those in the 18-50 age group (National Spinal Cord Injury Statistical Center (NSCISC) “Spinal Cord Injury Facts and Figures at a Glance” Birmingham: University of Alabama (2010). The injury process involves primary and secondary components (Fehlings et al. “Current status of clinical trials for acute spinal cord injury” Injury 36 Suppl 2:B113-22 (2005); Hall et al. “Neuroprotection and acute spinal cord injury: a reappraisal” Neurorx 1(1):80-100 (2004); Onose et al. “A review of published reports on neuroprotection in spinal cord injury” Spinal Cord 47(10):716-26 (2009). Primary injury occurs immediately after trauma and mainly involves axonal loss at the injury epicenter. Subsequent local inflammation induces secondary injury from the release of cytokines, activation of microglia, and post-traumatic ischemia (Tator et al. “Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75(1):15-26 (1991). Secondary injury leads to delayed necrosis and apoptosis resulting in further neuronal loss. In efforts to minimize secondary injury, several neuroprotection strategies have been investigated in randomized control trials. The most notable among these trials were the first and second National Acute Spinal Cord Injury Studies (NASCIS) (Bracken et al. “Efficacy of methylprednisolone in acute spinal cord injury” JAMA 251(1):45-52 (1984); Bracken et al. “A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study” N. Engl. J. Med. 322(20):1405-11 (1990). The results from both these trials, as well as many subsequent studies focusing on the different treatment strategies, have shown no benefit in secondary injury prevention.
The present invention overcomes these shortcomings by providing methods for promoting revascularization and/or reenervation of CNS lesions and for treating spinal cord injury. The methods may be accompanied by removal of existing scar tissue and/or prevention of scar tissue formation.